Gamma-Aminobutyric acid (GABA) transminase and L-glutamate decarboxylase are the two enzymes involved in the degradation and biosynthesis respectively of the neurotransmitter GABA. We have developed highly potent and specific kcat irreversible inactivators of these two enzymes. Gabaculine (5-amino-1,3-cyclohexadienylcarboylic acid) and derivatives inactivate the transaminase and alpha-trifluoromethyl glutamate and alpha-methyl dehydroglutamate inactivate the decarboxylase. This allows for the unique opportunity modulating the levels of this neurotransmitter in tissue culture and in vivo. We plan to study the neuropharmacological consequences of the inactivation of these two enzymes. The use of the inactivators will allow for the creation of models for molecular diseases in which either GABA cannot be synthesized or degraded. The relationship of these models to molecular diseases such as Huntington's Chorea or hypergabanuria is of great interest. The highly specific and potent GABA-transaminase inhibitors might be therapeutically useful in the treatment of Huntington's chorea, tardiv dyskenisia, and convulsive disorders whereas the glutamate decarboxylase inhibitors should allow for the determination of the role of this enzyme in these disease states. Gabaculine has already been shown to be a powerful anticonvulsant in animal tests. In tissue culture the role of these enzymes in gaba-ergic synapse formation and neuronal development will be studied. Finally, since glutamate decarboxylase can be taken as a marker for gaba-ergic neurons it is proposed to develop a new mapping technique for these neurons in culture and in vivo using highly radiolabeled decarboxylase inhibitors coupled with autoradiography.